Submissions for variant NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro)

dbSNP: rs727504356

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000475271	SCV001976468	likely pathogenic	Hypertrophic cardiomyopathy	2021-09-28	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro) variant has been identified in at least 13 probands with HCM (PM4_Moderate; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Walsh 2017 PMID: 27532257; Ambry pers. comm., GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.). Additionally, this variant was reported in a patient with suspected RCM/HCM as well as arrhythmia, who also carried the pathogenic NM_000257.4(MYH7):c.2167C>T p.(Arg723Cys) variant. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM4_Moderate, PM2, PM1, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000475271	SCV000204154	likely pathogenic	Hypertrophic cardiomyopathy	2019-07-23	criteria provided, single submitter	clinical testing	The p.Ala868Pro variant in MYH7 has been reported in at least 8 individuals with HCM (Millat 2010, Walsh 2017, LMM data, Invitae personal communication, ClinVar Variation ID 177847), including 1 individual with early-onset HCM who also carried a pathogenic variant in the MYBPC3 gene. It has also been reported to segregate with HCM in one affected family member (ClinVar submission SCV000924872.1). This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate.
GeneDx	RCV000766436	SCV000208486	likely pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 20624503, 29300372, 21310275, 17095604, 2062450, 20800588)
Invitae	RCV000475271	SCV000546246	pathogenic	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 868 of the MYH7 protein (p.Ala868Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 2062450, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 177847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622129	SCV000737025	likely pathogenic	Cardiovascular phenotype	2023-08-14	criteria provided, single submitter	clinical testing	The c.2602G>C (p.A868P) alteration is located in exon 22 (coding exon 20) of the MYH7 gene. This alteration results from a G to C substitution at nucleotide position 2602, causing the alanine (A) at amino acid position 868 to be replaced by a proline (P). _x000D_ _x000D_ for MYH7-related cardiomyopathies; however, its clinical significance for MYH7-related skeletal myopathies is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Millat, 2010; Walsh, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger, 2016; Walsh, 2017; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001189962	SCV001357362	likely pathogenic	Cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 868 in the myosin head/motor domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight unrelated individuals affected with hypertrophic cardiomyopathy (MID: 20624503, 27532257, 33495597; communication with external laboratories, ClinVar variation ID: 177847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000766436	SCV002563187	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003314568	SCV004014672	likely pathogenic	Hypertrophic cardiomyopathy 1	2023-04-26	criteria provided, single submitter	clinical testing	The MYH7 c.2602G>C (p.Ala868Pro) missense variant has been reported in at least four individuals with hypertrophic cardiomyopathy, one of whom also had a variant in the MYBPC3 gene (PMID: 27532257; 20624503). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. It is located in the head region of the protein, where missense variants are statistically more likely to be associated with hypertrophic cardiomyopathy (PMID: 27532257). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel and multiple other submitters in ClinVar. Based on the available evidence, the c.2602G>C (p.Ala868Pro) variant is classified as likely pathogenic for hypertrophic cardiomyopathy.
All of Us Research Program, National Institutes of Health	RCV000475271	SCV004844784	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 868 in the myosin head/motor domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight unrelated individuals affected with hypertrophic cardiomyopathy (MID: 20624503, 27532257, 33495597; communication with external laboratories, ClinVar variation ID: 177847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766436	SCV000924872	uncertain significance	not provided	2017-04-21	no assertion criteria provided	provider interpretation	This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Ala868Pro (A868P; c.2602G>C) in exon 22 of the MYH7 gene (NM_000257.2) Chromosome position: 14:23894055 C / G Based on the information reviewed below, including the presence in cases with HCM, the absence in general population controls, and the likely structural disruption this variant would cause to the protein, we classify it as a Variant of Uncertain Significance (VUS)-probably disease causing, concluding that it is highly suspicious but that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk relatives at this time. The Laboratory for Molecular Medicine and Invitae have both submitted it to ClinVar as a VUS. This variant has previously been reported in at least 3 individuals with a stated diagnosis of HCM. Alfares et al. from the Laboratory for Molecular Medicine reported it in 2015 in one person tested for HCM at their laboratory. Millat et al. (2010) reported it in 2 unrelated French probands clinically diagnosed with HCM. However, one of these individuals (diagnosed at one year of age) also had a missense variant in the MYBPC3 gene: p.Arg1022Pro (Millat et al. 2010). There is no published segregation data for Ala868Pro. However, in our patient’s family the variant does segregate with disease in this patient and her daughter who have both been clinically diagnosed with HCM. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Proline. However, this residue falls within the S2 subfragment of myosin (residues 848-1216; Colegrave and Peckham 2014), which is a highly repetitive amino acid sequence at the beginning of the rod domain that forms an alpha-helical coiled-coil structure. Proline is known to break alpha helices, and it could therefore disrupt the structure of this protein domain or disrupt the higher-order formation of sarcomere thick filaments. Alanine at this location is highly conserved across vertebrate species. The surrounding residues are also highly conserved. Nearby residue p.Arg870His is considered solidly Pathogenic by multiple submitters to ClinVar. In silico analysis with PolyPhen-2 predicts the Ala868Pro variant to be “Possibly Damaging” with a score of 0.929. According to Varsome.com: MutationTaster predicts it to be “Disease Causing” and SIFT predicts it to be “Damaging”. In total the variant has not been seen in >140,000 published controls and individuals from publicly available population datasets. The variant was not observed in published controls: 200 French Caucasians (Millat et al. 2010). This variant is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Our patient’s ancestry is Latino. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5778 “Latino” individuals. This variant is not present in ExAC. There is good coverage at this site: Almost all individuals are covered at 30x, with mean and median coverage close to 80x. These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. This variant is also not present in the gnomAD database, which is an expansion of ExAC to include variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. There is 1 Latino individual in gnomAD with a different amino acid change at this location: p.Ala868Ser.